Pharmacogenetic Morphine Spine Study

Safe and effective analgesia is an important unmet medical need in children. Despite efforts
to promote non-pharmacologic interventions, drug treatment remains the standard of care for
children experiencing severe pain following surgery. Inadequate pain relief after invasive
surgery, and side effects from analgesics such as morphine occur frequently in up to 50% of
children. A study of patient-controlled analgesia morphine use after spine surgery in
adolescents observed a 45% incidence of postoperative nausea and vomiting 15% incidence of
pruritis and 7% incidence of respiratory depression. Among the drugs available, the opioids,
specifically morphine is the most commonly employed. Morphine has a narrow therapeutic index,
with the most fatal toxicity being respiratory depression. For morphine, like most opioids,
there is a fine balance in dosing regimen between optimal pain control and safety in terms of
decreasing morphine's respiratory depressant/ sedative side effects. Inadequate pain relief
and analgesic side effects have major clinical, behavioral and economic consequences. Neither
evidence-based dosing guidelines nor rigorous documentation of therapeutic benefit for
morphine has been ascertained in the pediatric patient population. Despite aggressive pain
management after spine surgery, findings showed that neither children's pain nor their
analgesic use diminished significantly over time. As such, there is a critical knowledge gap
in the medical literature that significantly impacts the pediatric pain management. In
recognition of this therapeutic challenge the investigators plan to evaluate the determinants
of inter-individual differences in opioid analgesic responsiveness and adverse effects in
children. Adolescents following spine surgery have a great variability in morphine
requirements with greater use as they became older. Analgesic dosing is dependent on
appreciation of the interplay between pharmacokinetics, pharmacodynamics and therapeutics.
These factors are often poorly understood, where the effective control of procedural pain for
example, remains problematic. Suitable pharmacological alternatives to opioid treatment for
moderate to severe pain in children after surgery are limited and consequently there is a
need for a critical evaluation of the existing opioids and research reports.

Recently a number of small studies have shown the association of single nucleotide
polymorphism in genes in the pain pathway, with altered pain response to a stimulus or
altered response to opioids following a painful procedure. Age, gender, cultural influences,
anxiety, type of surgical procedure and genetic factors can all influence the response.

Inclusion Criteria:

- Children aged 10 to 18, inclusive, years of age

- Diagnosis of Idiopathic scoliosis, kyphosis and/or kyphoscoliosis

- Scheduled for spine fusion

Exclusion Criteria:

- Known hypersensitivity to morphine

- Patients on chronic pain medication.

- Pregnant or breastfeeding females.

- Children with a history of or active renal or liver disease.

- Concomitant use of medication known to induce or inhibit CYP2D6 activity including
paroxetine, fluoxetine, cimetidine, duloxetine or methadone.

- Non-English speaking patients.

- Developmental delay.

- Children who have problems with pupil or pupillary reaction due to disease (such as
amyloidosis, bilateral Horner's syndrome, familial dysautonomia, other major
neurological disorders) or preoperative medications influencing pupillary size
(anti-cholinergic, narcotic medications such as codeine in cough syrup) will be
recruited but pupillometry will be deferred.